http://www.celldiv.com The latest research articles published by Cell Division 2010-03-10T00:00:00Z This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ Maintenance of genomic integrity is important for cellular viability and proliferation. During DNA replication, cells respond to replication stress by activating checkpoint pathways that stabilize replication forks and prevent cell cycle progression. The Saccharomyces cerevisiae F-box protein Dia2 is a ubiquitin ligase component required for genomic stability and may help replication complexes negotiate damaged DNA or natural fragile sites. We recently implicated Dia2 in the replication stress response. We demonstrated that Dia2 is targeted for ubiquitin-mediated proteolysis and that activation of the S-phase checkpoint inhibits Dia2 protein turnover. S-phase checkpoint mutants fail to stabilize the Dia2 protein and checkpoint mutants that lack Dia2 exhibit increased sensitivity to replication stress. We also showed that Dia2 protein turnover is not the result of an autocatalytic mechanism. Instead, an N-terminal 20 amino acid motif that is also required for nuclear localization is necessary for Dia2 proteolysis. Dia2 mutants lacking this motif but modified with an exogenous strong nuclear localization signal are both nuclear and stable and disrupt cell cycle dynamics. In summary, our studies suggest that inhibition of Dia2 proteolysis is a novel target of the S-phase checkpoint. We think that this work will help to identify the mechanisms that function downstream of checkpoint activation and that intersect with cell cycle control pathways. http://www.celldiv.com/content/5/1/8 Deanna Koepp Cell Division 2010, 5:8 2010-03-10T00:00:00Z doi:10.1186/1747-1028-5-8 Cell Division 1747-1028 5 8 2010-03-10T00:00:00Z XML Regulation of the repair of DNA double-strand breaks by homologous recombination is extremely important for both cell viability and the maintenance of genomic integrity. Modulation of double-strand break repair in the yeast Saccharomyces cerevisiae involves controlling the recruitment of one of the central recombination proteins, Rad52, to sites of DNA lesions. The Rad52 protein, which plays a role in strand exchange and the annealing of single strand DNA, is positively regulated upon entry into S phase, repressed during the intra-S phase checkpoint, and undergoes posttranslational modification events such as phosphorylation and sumoylation. These processes all contribute to the timing of Rad52 recruitment, its stability and function. Here, we summarize the regulatory events affecting the Rad52 protein and discuss how this regulation impacts DNA repair and cell survival. http://www.celldiv.com/content/5/1/7 Jacqueline Barlow Rodney Rothstein Cell Division 2010, 5:7 2010-02-23T00:00:00Z doi:10.1186/1747-1028-5-7 Cell Division 1747-1028 5 7 2010-02-23T00:00:00Z XML Pancreatic β-cells are metabolic sensors involved in the control of glucose homeostasis. This particular cell type controls insulin secretion through a fine-tuned process, which dregulation have important pathological consequences, such as observed during type 2 diabetes. We recently implicated E2F1 in the control of glucose homeostasis. First we showed that E2f1-/- mice have decreased pancreatic size, as the result of impaired postnatal pancreatic growth. We observed in this study that E2F1 was highly expressed in non-proliferating pancreatic β-cells, suggesting that E2F1, besides the control of β-cell number could have a role in pancreatic β-cell function. We demonstrate in our recent study, both in vitro and in vivo that E2F1 directly regulates the expression of Kir6.2, a key component of the KATP channel involved in the regulation of glucose-induced insulin secretion in pancreatic β-cells. Expression of Kir6.2 is lost in pancreas of E2f1-/- mice, resulting in insulin secretion defects in these mice. Furthermore, we demonstrated by in tissue chromatin immunoprecipitation analysis that regulation of Kir6.2 expression by E2F1 follows the same regulatory pathway that the classical E2F1 target genes, implicating the participation of CDK4 and retinoblastoma protein. Moreover, in this context, E2F1 transcriptional activity is regulated by glucose and insulin through the CDK4-dependent inactivation of the pRB protein. In summary we provide evidence that the CDK4-pRB-E2F1 regulatory pathway is involved in glucose homeostasis. In our recent study we decipher a new function for these factors in the control of insulin secretion and open up new avenues for the treatment of metabolic diseases, in particular type 2 diabetes. http://www.celldiv.com/content/5/1/6 Lluis Fajas Emilie Blancher Jean-Sebastien Annicotte Cell Division 2010, 5:6 2010-02-05T00:00:00Z doi:10.1186/1747-1028-5-6 Cell Division 1747-1028 5 6 2010-02-05T00:00:00Z XML Gradients are used in a number of biological systems to transmit spatial information over a range of distances. The best studied are morphogen gradients where information is transmitted over many cell lengths. Smaller mitotic gradients reflect the need to organize several distinct events along the length of the mitotic spindle. The intracellular gradients that characterize mitosis are emerging as important regulatory paradigms. Intracellular gradients utilize intrinsic auto-regulatory feedback loops and diffusion to establish stable regions of activity within the mitotic cytosol. We review three recently described intracellular mitotic gradients. The Ran GTP gradient with its elaborate cascade of nuclear transport receptors and cargoes is the best characterized, yet the dynamics underlying the robust gradient of Ran-GTP have received little attention. Gradients of phosphorylation have been observed on Aurora B kinase substrates both before and after anaphase onset. In both instances the phosphorylation gradient appears to result from a soluble gradient of Aurora B kinase activity. Regulatory properties that support gradient formation are highlighted. Intracellular activity gradients that regulate localized mitotic events bare several hallmarks of self-organizing biologic systems that designate spatial information during pattern formation. Intracellular pattern formation represents a new paradigm in mitotic regulation. http://www.celldiv.com/content/5/1/5 Brian Fuller Cell Division 2010, 5:5 2010-01-29T00:00:00Z doi:10.1186/1747-1028-5-5 Cell Division 1747-1028 5 5 2010-01-29T00:00:00Z XML Senescence and mitotic catastrophe (MC) are two distinct crucial non-apoptotic mechanisms, often triggered in cancer cells and tissues in response to anti-cancer drugs. Chemotherapeuticals and myriad other factors induce cell eradication via these routes. While senescence drives the cells to a state of quiescence, MC drives the cells towards death during the course of mitosis. The senescent phenotype distinguishes tumor cells that survived drug exposure but lost the ability to form colonies from those that recover and proliferate after treatment. Although senescent cells do not proliferate, they are metabolically active and may secrete proteins with potential tumor-promoting activities. The other anti-proliferative response of tumor cells is MC that is a form of cell death that results from abnormal mitosis and leads to the formation of interphase cells with multiple micronuclei. Different classes of cytotoxic agents induce MC, but the pathways of abnormal mitosis differ depending on the nature of the inducer and the status of cell-cycle checkpoints. In this review, we compare the two pathways and mention that they are activated to curb the growth of tumors. Altogether, we have highlighted the possibilities of the use of senescence targeting drugs, mitotic kinases and anti-mitotic agents in fabricating novel strategies in cancer control. http://www.celldiv.com/content/5/1/4 Richa Singh Jasmine George Yogeshwer Shukla Cell Division 2010, 5:4 2010-01-21T00:00:00Z doi:10.1186/1747-1028-5-4 Cell Division 1747-1028 5 4 2010-01-21T00:00:00Z XML Apoptosis induced by DNA damage is an important mechanism of tumor suppression and it is significant also in cancer chemotherapy. Mammalian cells activate the pathways of p53 to induce apoptosis of cells harboring irreparable DNA damages. While p53 induces expression of various pro-apoptotic genes and directly participates in the disruption of mitochondrial membrane polarization, it also increases expression of the cell cycle inhibitor p21 that is a dominant inhibitor of caspase-activation and apoptosis. Here we discuss how Damaged-DNA Binding Protein-2 (DDB2) subdues the level of p21 in cells harboring irreparable DNA damage to support activation of the caspases. We speculate a model in which DDB2 detects and couples the presence of un-repaired DNA damages to the proteolysis of p21, leading to the induction of apoptosis. http://www.celldiv.com/content/5/1/3 Srilata Bagchi Pradip Raychaudhuri Cell Division 2010, 5:3 2010-01-19T00:00:00Z doi:10.1186/1747-1028-5-3 Cell Division 1747-1028 5 3 2010-01-19T00:00:00Z XML The highly conserved E-type cyclins are core components of the cell cycle machinery, facilitating the transition into S phase through activation of the cyclin dependent kinases, and assembly of pre-replication complexes on DNA. Cyclin E1 and cyclin E2 are assumed to be functionally redundant, as cyclin E1-/- E2-/- mice are embryonic lethal while cyclin E1-/- and E2-/- single knockout mice have primarily normal phenotypes. However more detailed studies of the functions and regulation of the E-cyclins have unveiled potential additional roles for these proteins, such as in endoreplication and meiosis, which are more closely associated with either cyclin E1 or cyclin E2. Moreover, expression of each E-cyclin can be independently regulated by distinct transcription factors and microRNAs, allowing for context-specific expression. Furthermore, cyclins E1 and E2 are frequently expressed independently of one another in human cancer, with unique associations to signatures of poor prognosis. These data imply an absence of co-regulation of cyclins E1 and E2 during tumorigenesis and possibly different contributions to cancer progression. This is supported by in vitro data identifying divergent regulation of the two genes, as well as potentially different roles in vivo. http://www.celldiv.com/content/5/1/2 C Elizabeth Caldon Elizabeth Musgrove Cell Division 2010, 5:2 2010-01-17T00:00:00Z doi:10.1186/1747-1028-5-2 Cell Division 1747-1028 5 2 2010-01-17T00:00:00Z XML Oncogenic proliferative signals are coupled to a variety of growth inhibitory processes. In cultured primary human fibroblasts, for example, ectopic expression of oncogenic Ras or its downstream mediator initiates cellular senescence, the state of irreversible cell cycle arrest, through up-regulation of cyclin-dependent kinase (CDK) inhibitors, such as p16INK4a. To date, much of our current knowledge of how human p16INK4a gene expression is induced by oncogenic stimuli derives from studies undertaken in cultured primary cells. However, since human p16INK4a gene expression is also induced by tissue culture-imposed stress, it remains unclear whether the induction of human p16INK4a gene expression in tissue-cultured cells truly reflects an anti-cancer process or is an artifact of tissue culture-imposed stress. To eliminate any potential problems arising from tissue culture imposed stress, we have recently developed a bioluminescence imaging (BLI) system for non-invasive and real-time analysis of human p16INK4a gene expression in the context of a living animal. Here, we discuss the molecular mechanisms that direct p16INK4a gene expression in vivo and its potential for tumor suppression. http://www.celldiv.com/content/5/1/1 Naoko Ohtani Kimi Yamakoshi Akiko Takahashi Eiji Hara Cell Division 2010, 5:1 2010-01-14T00:00:00Z doi:10.1186/1747-1028-5-1 Cell Division 1747-1028 5 1 2010-01-14T00:00:00Z XML Cancer is a multifaceted disease that results from dysregulated normal cellular signaling networks caused by genetic, genomic and epigenetic alterations at cell or tissue levels. Uncovering the underlying protein signaling network changes, including cell cycle gene networks in cancer, aids in understanding the molecular mechanism of carcinogenesis and identifies the characteristic signaling network signatures unique for different cancers and specific cancer subtypes. The identified signatures can be used for cancer diagnosis, prognosis, and personalized treatment. During the past several decades, the available technology to study signaling networks has significantly evolved to include such platforms as genomic microarray (expression array, SNP array, CGH array, etc.) and proteomic analysis, which globally assesses genetic, epigenetic, and proteomic alterations in cancer. In this review, we compared Pathway Array analysis with other proteomic approaches in analyzing protein network involved in cancer and its utility serving as cancer biomarkers in diagnosis, prognosis and therapeutic target identification. With the advent of bioinformatics, constructing high complexity signaling networks is possible. As the use of signaling network-based cancer diagnosis, prognosis and treatment is anticipated in the near future, medical and scientific communities should be prepared to apply these techniques to further enhance personalized medicine. http://www.celldiv.com/content/4/1/20 David Zhang Fei Ye Ling Gao Xiaoliang Liu Xin Zhao Yufang Che Hongxia Wang Libo Wang Josephine Wu Dong Song Wei Liu Hong Xu Bo Jiang Weijia Zhang Jinhua Wang Peng Lee Cell Division 2009, 4:20 2009-10-28T00:00:00Z doi:10.1186/1747-1028-4-20 Cell Division 1747-1028 4 20 2009-10-28T00:00:00Z XML Regulation of gene expression is essential to all aspects of physiological processes in single-cell as well as multicellular organisms. It gives ultimately cells the ability to efficiently respond to extra- and intracellular stimuli participating in cell cycle, growth, differentiation and survival. Regulation of gene expression is executed primarily at the level of transcription of specific mRNAs by RNA polymerase II (RNAPII), typically in several distinct phases. Among them, transcription elongation is positively regulated by the positive transcription elongation factor b (P-TEFb), consisting of CDK9 and cyclin T1, T2 or K. P-TEFb enables transition from abortive to productive transcription elongation by phosphorylating carboxyl-terminal domain (CTD) in RNAPII and negative transcription elongation factors. Over the years, we have learned a great deal about molecular composition of P-TEFb complexes, their assembly and their role in transcription of specific genes, but function of P-TEFb in other physiological processes was not apparent until just recently. In light of emerging discoveries connecting P-TEFb to regulation of cell cycle, development and several diseases, I would like to discuss these observations as well as future perspectives. http://www.celldiv.com/content/4/1/19 Jiri Kohoutek Cell Division 2009, 4:19 2009-09-02T00:00:00Z doi:10.1186/1747-1028-4-19 Cell Division 1747-1028 4 19 2009-09-02T00:00:00Z XML